Between 1% and 3% of U. S. women suffer recurrent miscarriages. Although the cause of recurrent miscarriages in most women is unknown, an immune mechanism involving inappropriate and injurious recognition of the conceptus by the mother's immune system has been proposed. We have recently developed data in murine models indicating that innate immune mechanisms trigger abortion. Specifically, we have identified a novel role for complement activation as an early effector in the pathway leading to pregnancy loss associated with placental inflammation. Our work shows that complement activation is a central mechanism contributing to antiphospholipid antibody-induced pregnancy loss and fetal growth restriction and that complement activation is required for and precedes increases in TNF-alpha. In this application, we will test the hypothesis that complement activation is a necessary intermediary event in the pathogenesis of fetal loss in murine models of immunologically-mediated abortion representing both peri-implantation and postimplantation loss. Our overall goals are to elucidate the complement pathways that mediate recurrent spontaneous abortion and to define targets for interventions to prevent recurrent human miscarriage. Accordingly, our aims are: [unreadable] [unreadable] Aim 1. To define the role of complement in fetal loss in the DBA/2-mated female CBA/J murine model of spontaneous abortion. (a) To determine the temporal relationships between deposition of C3 (and of other complement components) and infiltration of inflammatory cells and production of TNF-q within decidua; (b) To identify the pathway(s) that initiate(s) complement activation and lead to C3 deposition in the decidua using complement deficient mice and specific complement inhibitors; (c) To determine whether diminished expression of murine complement regulatory proteins occurs in decidua and contributes to local complement activation; (d) To identify the complement pathway activation products and receptors that mediate fetal injury; (e) To determine which cellular and cytokine mediators of fetal loss contribute to deleterious complement activation in the deciduas. [unreadable] [unreadable] Aim 2. To define the role of complement in fetal loss in the DBA/2-mated TNF-a-treated female C57BL/6 model and to identify the specific complement activation products that mediate in vivo tissue injury and fetal loss. (a) To determine whether C3 is deposited within deciduas; whether C3 activation is required for abortion; and the relationship between TNF-alpha treatment, C3 deposition, and cellular infiltration; (b) To define the complement components or receptors that contribute to cytokine-dependent abortion using complement deficient mice and specific complement inhibitors [unreadable] [unreadable] If complement activation is a necessary mechanism in repeated pregnancy loss, elucidating the roles of specific complement components will provide a basis for developing new therapies, a rationale for choosing among them, and the capacity to improve patient outcomes. In addition, our studies will provide insights into mechanisms by which complement-induces disease and suggest means to prevent, arrest, or modify complement-mediated inflammatory disorders. [unreadable] [unreadable]